CN1890213A - Process for preparing N-amino-substituted heterocyclic compounds - Google Patents

Abstract

The present invention discloses and claims an improved process for the preparation of N-amino nitrogen heterocycles. In one embodiment of the invention, the compounds of the formula (VI) are prepared starting from the corresponding indole derivatives by N-amination and subsequent formation of the hydrazone by reaction with a ketone compound in a single step. Further reduction of the hydrazone and subsequent coupling with a pyridine compound provides a compound of formula VI or a suitable salt thereof.

Description

Process for preparing N-amino substituted heterocyclic compounds

Background of the Invention

field of invention

The present invention relates to a method for N-amination of nitrogen-containing heterocyclic compound series. More particularly, the present invention relates to an improved process for the preparation of N-aminoindoles by N-amination of indoles. The present invention also relates to an improved process for the preparation of N-(n-propyl)-N-(3-fluoro-4-pyridyl)-1H-3-methyl-indol-1-amine and products derived therefrom .

Description of prior art

A variety of N-amino substituted nitrogen heterocyclic compounds have been used as intermediates in the preparation of various organic compounds, especially mainly for pharmaceutical applications. A particularly important class of nitrogen heterocycles are the N-aminoindoles. It has been reported in the literature that indole can generally be synthesized by adding hydroxylamine-O-sulfonic acid (HOSA) to indole in portions in the presence of excess potassium hydroxide in a solvent such as dimethylformamide (DMF). N-amination of carbazoles and other nitrogen heterocyclic substances such as carbazole and pyrrole, see for example Somei, M.; Natsume, M. Tetrahedron Letters 1974, 461. Similar methods for the N-amination of, for example, indoles are described in US Patent No. 5,459,274, the entire contents of which references are hereby incorporated by reference.

However, the above methods have some limitations and are disadvantageous for the preparation of some N-hydroindoles especially with respect to the large-scale and commercial synthesis of N-aminoindoles. For example, adding hygroscopic HOSA in portions as a solid is problematic and not practical. Additionally, the reaction must be performed under heterogeneous conditions, resulting in unacceptably low product yields. In practice, product yields are usually on the low level of about 40% and can generally vary depending on the surface area and mass of potassium hydroxide used and the stirring efficiency of the reaction medium. Therefore, this method is not suitable for scale-up operations. On top of that a large excess of base is usually used, so there is necessarily an excessive waste disposal problem after neutralization and processing of the product, thus making the process uneconomical for commercial operation.

It is also disclosed in the literature that the N-amination of hexamethyleneimine can be carried out using HOSA in the presence of aqueous solvents and inorganic bases, see eg EP Patent Application No. 0249452, the entire content of which is hereby incorporated by reference. Inorganic bases disclosed therein include alkali metal hydroxides and alkaline earth metal hydroxides. In particular, it is disclosed in this method that N-amination can be carried out by simultaneously feeding an aqueous solution of HOSA and an aqueous solution of sodium hydroxide to an aqueous solution of hexamethyleneimine. However, this method similarly suffers from all the disadvantages described above, and in addition this method is specifically applicable to hexamethyleneimine - which is a more complex compound than many other nitrogen heterocycles such as indoles, carbazoles, pyrroles Wait for a stronger base. Nevertheless, the reported product yields are also very low. Therefore, there is a need for an improved method for the N-amination of nitrogen-containing heterocyclic compounds.

As noted above, the N-aminonitrogen heterocyclic compounds so formed are useful as intermediates for the formation of N-alkylamino nitrogen-containing compounds such as N-alkylaminoindoles. In general, N-alkylation of amino groups can be carried out using an alkylating agent such as a haloalkane in the presence of a base. However, such alkylation reactions often result in significant amounts of by-products resulting from competing alkylation of heterocycles and are therefore undesirable, see eg US Patent No. 5,459,274. In addition, such alkylation processes also generate excessive by-products such as basic halides, which must be disposed of, making them unsuitable for industrial scale-up operations.

It was therefore an object of the present invention to provide a novel homogeneous process for the N-amination of a wide variety of nitrogen heterocycles.

Another object of the present invention is to provide a process for the N-amination of nitrogen heterocyclic compounds involving organic bases, whereby N-aminoheterocyclic compounds are prepared in high yield and in high purity.

Yet another object of the present invention is to provide a novel N-alkylation process which does not result in any by-products, thereby providing N-alkylaminoheterocyclic compounds of high purity.

Other objects and further scope of applicability of the present invention will be apparent from the following detailed description.

Summary of the invention

It has now been found that the N-amination of a wide variety of nitrogen heterocycles can be carried out using organic bases and organic solvents, such as aprotic solvents, in a homogeneous medium. Therefore, according to one aspect of the present invention, a kind of method for preparing formula II compound is provided:

The method of this aspect of the invention comprises the steps of:

(a) in step (a), prepare a solution of hydroxylamine-O-sulfonic acid (HOSA) in a suitable organic solvent;

(b) in step (b), preparing a solution of a suitable base in a suitable organic solvent;

(c) in step (c), a solution of the compound of formula I is prepared in a suitable organic solvent;

(d) finally in step (d), the solution prepared in step (a) and the solution prepared in step (b) are simultaneously and proportionally added to the step ( c) in the prepared solution, thereby providing the compound of formula (II) with high purity and high yield,

in

R is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, benzyloxy or fluoroalkyl or fluoroalkoxy of the formula C _n H _x F _y or OC _n H _x F _y , wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n+1;

R ₁ and R ₂ are the same or different and are independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, benzyloxy or the formula C _n H _x F _y or OC _n H _x F fluoroalkyl or fluoroalkoxy of _y , wherein n is an integer of 1 to 4, x is an integer of 0 to 8, y is an integer of 1 to 9, and the sum of x and y is 2n+1; or

R ₁ and R ₂ together with the carbon atoms to which they are attached form a C ₅ -C ₈ ring; and

m is 1 or 2.

In another aspect of the present invention, there is also provided another process for preparing the compound of formula II as described herein. The method of this aspect of the invention comprises the following steps. In step (a), a solution of hydroxylamine-O-sulfonic acid and a compound of formula I as described herein is prepared in a suitable organic solvent. In step (b), a solution of a suitable base is prepared in a suitable organic solvent. In step (c), the solution prepared in step (a) is simultaneously and proportionally contacted with the solution prepared in step (b) at a suitable reaction temperature to provide formula (II) in high purity and high yield compound. wherein R, R ₁ , R ₂ and m are as defined above.

In another aspect of the present invention, there is also provided a method for preparing the compound of formula IV:

In this aspect of the invention, the method involves the following. A solution of hydroxylamine-O-sulfonic acid in a suitable organic solvent and a solution of a suitable base in a suitable organic solvent are simultaneously and proportionally added to the formula as described herein in a suitable organic solvent at a suitable reaction temperature A solution of a compound of I, wherein a compound of formula (I) as described herein is packed in a suitable reaction vessel. This reaction can provide compounds of formula (II) as described herein.

The resulting N-aminoindole compound (II) is then reacted with a compound of formula (III) in the same reaction vessel to provide a compound of formula (IV).

wherein R, R ₁ , R ₂ and m are as defined above, and R ₃ and R ₄ are the same or different and are independently selected from hydrogen or C ₁ -C ₄ alkyl.

Finally, in another aspect of the present invention there is also provided a method for preparing the compound of formula VI:

In this aspect of the invention, the method comprises the steps of:

In step (a), the compound of formula (IV) as described herein is first prepared substantially according to the steps of the above embodiments. That is, at a suitable reaction temperature, a solution of hydroxylamine-O-sulfonic acid in a suitable organic solvent and a suitable base solution in a suitable organic solvent are simultaneously and proportionally added to a solution of the compound of formula I in a suitable organic solvent , wherein a compound of formula (I) as described herein is packed in a suitable reaction vessel. This reaction provides compounds of formula (II) as described herein. The resulting N-aminoindole compound (II) is then reacted with a compound of formula (III) in the same reaction vessel to provide a compound of formula (IV).

In step (b) of the process of the invention, a compound of formula (IV) is reacted with a suitable reducing agent to provide a compound of formula (V):

Finally, in step (c) of the process of the invention, the compound of formula (V) is then combined with the compound of formula (VII) in the presence of hydrochloric acid

Reaction to provide the compound of formula (VI) as its hydrochloride salt. wherein R, R ₁ , R ₂ , R ₃ , R ₄ and m are as described above. R ₅ is hydrogen, nitro, amino, halogen, C _1-4 alkyl, C _1-4 alkanoylamino, phenyl-C _1-4 alkanoylamino, phenylcarbonylamino, alkylamino or phenyl- C _1-4 alkylamino; X is halogen; n is 1 or 2, and p is 0 or 1.

In another aspect of the present invention there is also provided a compound of formula (IV), wherein said substituents are as described herein, with the proviso that when R and _R3 are hydrogen, _R4 is not hydrogen or methyl.

Detailed description of the invention

The terms used herein have the following meanings:

The expression "C _1-4 alkyl" as used herein includes methyl and ethyl as well as linear or branched propyl and butyl. Specific alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. Derived expressions such as "C _1-4 alkoxy", "phenyl-C _1-4 alkylamino", "amino-C _1-4 alkyl", "C _1-4 alkyl Amino", "mono- or di-C _1-4 alkylamino C _1-4 alkyl", "diphenyl-C _1-4 alkyl", "phenyl-C _1-4 alkyl", "benzene "Carbonyl-C _1-4 alkyl" and "phenoxy-C _1-4 alkyl".

The expression "C _1-6 alkanoyl" as used herein shall have the same meaning as "C _1-6 acyl", which may also be structurally represented as "R-CO-", wherein R is as defined herein is C _1-5 alkyl. In addition, "C _1-5 alkylcarbonyl" shall have the same meaning as C _1-6 acyl. In particular, "C _1-6 acyl" would be formyl, acetyl or ethanoyl, propionyl, n-butyryl and the like. Derived expressions such as "C _1-4 acyloxy", "C _1-4 acyloxyalkyl", "C _1-6 alkanoylamino", "phenyl-C _1-6 alkane" can be understood accordingly Acylamino".

The expression "C _1-6 perfluoroalkyl" used herein means that all hydrogen atoms in the alkyl group are replaced by fluorine atoms. Illustrative examples include trifluoromethyl and pentafluoroethyl, and linear or branched heptafluoropropyl, nonafluorobutyl, undecafluoropentyl and tridecafluorohexyl. The derived expression "C _1-6 perfluoroalkoxy" is to be understood accordingly.

The expression "heteroaryl" as used herein includes all known heteroatom-containing aryl groups. Representative 5-membered heteroaryl groups include furyl, thienyl or thiophenyl, pyrrolyl, isopyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, and the like. Representative 6-membered heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like. Representative examples of bicyclic heteroaryl groups include benzofuryl, benzothienyl, indolyl, quinolinyl, isoquinolyl, and the like groups.

The expression "heterocycle" as used herein includes all known heteroatom-containing cyclic groups. Representative 5-membered heterocyclic groups include tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, 2-thiazolinyl, tetrahydrothiazolyl, tetrahydrooxazolyl, and the like. Representative 6-membered heterocyclic groups include piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like. Many other heterocyclic groups include, but are not limited to, aziridinyl, azepanyl, diazepanyl, diazabicyclo[2.2.1]hept-2-yl, and triazepanyl Heptyl (triazocanyl) and the like.

"Halogen" or "halo" refers to chlorine, fluorine, bromine and iodine.

"Patient" as used herein refers to warm-blooded animals such as rats, mice, dogs, cats, guinea pigs and primates such as humans.

The term "pharmaceutically acceptable salt" as used herein means that the salts of the compounds of the present invention are useful in medical applications. However, other salts may also be used in the preparation of the compounds according to the invention or pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of compounds of the invention include acid addition salts which may be formed, for example, by mixing a solution of a compound according to the invention with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid , hydrobromic acid, sulfuric acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinic acid, glutaric acid, Acetic acid, salicylic acid, cinnamic acid, 2-phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid, or phosphoric acid. Acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate may also be formed. The salts so formed may also exist as mono- or di-acid salts, and may exist in hydrated form or may be substantially anhydrous. In addition, where a compound of the present invention bears an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts such as sodium or potassium; alkaline earth metal salts such as calcium or magnesium; Ligand-formed salts such as quaternary ammonium salts.

The expression "stereoisomer" is a generic term for all isomers of individual molecules which differ only in the orientation of their atoms in space. In general, it includes mirror image isomers (enantiomers) which usually form as a result of at least one asymmetric center. In cases where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereomers, and certain individual molecules may also exist as geometric isomers (cis/trans) exist. Similarly, certain compounds of the present invention may exist as a mixture of two or more structurally distinct, rapidly equilibrating forms, commonly referred to as tautomers. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers wait. It should be understood that all such isomers and mixtures thereof in any ratio are included within the scope of the present invention.

In a broad sense, the term "substituted" is considered to include all permissible substituents of organic compounds. In several specific embodiments disclosed herein, the term "substituted" refers to being substituted by one or more substituents independently selected from the following groups: C _1-6 alkyl, C _2-6 alkenyl , C _1-6 perfluoroalkyl, phenyl, hydroxyl, -CO ₂ H, ester, amide, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkyl, C ₁ -C ₆ perfluoro Alkoxy, -NH ₂ , Cl, Br, I, F, -NH-lower alkyl and -N(lower alkyl) ₂ . However, any other suitable substituents known to those skilled in the art may also be used in these embodiments.

Therefore, according to one aspect of the present invention, there is provided a method for preparing various N-amino substituted heterocyclic compounds. Thus in one broad aspect of the invention, any nitrogen heterocyclic compound of formula (IA) can be used to prepare the corresponding N-amino-heterocyclic compound, as shown in Scheme 1 .

plan 1

Representative examples of monocyclic nitrogen heterocyclic compounds of formula (IA) useful in the methods of the invention include, but are not limited to, substituted or unsubstituted pyrroles, pyrazoles, imidazoles, 1,2,3-triazoles, 1,2, 4-triazole etc. Representative examples of bicyclic nitrogen heterocyclic compounds of formula (IA) useful in the methods of the invention include, but are not limited to, substituted or unsubstituted indole, 4, 5, 6 or 7-aza-indole, purine, indazole , 4, 5, 6 or 7-aza-indazole, benzimidazole, 4,7-diazaindole and various other isomeric diazaindole, etc. Representative examples of tricyclic nitrogen heterocyclic compounds of formula (IA) that may be used in the methods of the present invention include, but are not limited to, substituted or unsubstituted carbazoles or a variety of well-known heteroatom-substituted carbazoles. As defined above, any possible substituents may be used in the case of the above substituted heterocyclic compounds, provided that these substituents do not interfere with the process of the invention.

Therefore, in a particular embodiment of the present invention there is provided a process for the preparation of compounds of formula II:

The method of this aspect of the invention comprises the steps of:

(a) in step (a), prepare a solution of hydroxylamine-O-sulfonic acid (HOSA) in a suitable organic solvent;

(b) in step (b), preparing a solution of a suitable base in a suitable organic solvent;

(c) in step (c), a solution of the compound of formula I is prepared in a suitable organic solvent;

(d) finally in step (d), the solution prepared in step (a) and the solution prepared in step (b) are simultaneously and proportionally added to the step ( c) in the prepared solution, thereby providing the compound of formula (II) with high purity and high yield,

in

R is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, benzyloxy or fluoroalkyl or fluoroalkoxy of the formula C _n H _x F _y or OC _n H _x F _y , wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n+1;

R ₁ and R ₂ are the same or different and are independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, benzyloxy or the formula C _n H _x F _y or OC _n H _x F fluoroalkyl or fluoroalkoxy of _y , wherein n is an integer of 1 to 4, x is an integer of 0 to 8, y is an integer of 1 to 9, and the sum of x and y is 2n+1; or

R ₁ and R ₂ together with the carbon atoms to which they are attached form a C ₅ -C ₈ ring; and

m is 1 or 2.

It should be noted that the compounds of formula (II) may be prepared using the procedures as described hereinabove, not necessarily in different reaction vessels but essentially using these steps in the same reaction vessel. Also, the order of addition of reactants can be altered, if necessary, by altering the order of these steps.

In one aspect of the method of the invention, any suitable organic solvent known to those skilled in the art may be used in steps (a) and (b) of the method of the invention. Specific types of organic solvents that can be used broadly include polar aprotic solvents as well as various nonpolar aprotic solvents or mixtures thereof. As used herein, an aprotic organic solvent means that the solvent is neither a proton donor nor a proton acceptor. In general, aprotic solvents are more suitable for steps (a) and (b) of the process of the invention.

Representative examples of aprotic solvents suitable for the process of the invention include, but are not limited to, N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), hexamethylphosphoramide (HMPA), etc. Mixtures of these solvents in arbitrary proportions can also be used. Examples of non-polar organic solvents include, but are not limited to, tetrahydrofuran (THF), n-hexane, n-heptane, petroleum ether, and the like. A variety of halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like can also be used. Also other combinations of any polar and non-polar solvents can be used, such as NMP/hexane, NMP/heptane, etc.

As stated, the process of the invention uses a base in step (b) of the process of the invention. In general, any base that produces the desired effect can be used in this step of the process of the invention. It is generally advantageous in this step to use organic bases, especially organic bases which are soluble in the solvent used. Therefore, the reaction can proceed in a homogeneous manner. Additionally, bases having a pKa value at least about the same as that of indole are more suitable for this step of the method of the invention.

Suitable organic bases for this step include alkali metal alkoxides. Examples of suitable alkali metal alkoxides include, but are not limited to, lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium t-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, Potassium isopropoxide, potassium tert-butoxide, cesium methoxide, cesium ethoxide, cesium isopropoxide and cesium tert-butoxide, etc. Mixtures of these organic bases can also be used. Potassium tert-butoxide has been found to be a particularly suitable alkali metal alkoxide in the practice of the process of the invention.

In step (c) of the process according to the invention, the solvent used is also an aprotic solvent. Any of the aprotic solvents listed above may be used in this step of the process of the invention. The same solvents as used in steps (a) and (b) can also be used in this step. For example, such aprotic solvents include, but are not limited to, NMP, DMF, DMAc, etc. and/or mixtures thereof.

Any reaction temperature that produces the desired result can be employed in the process of the invention. In general, suitable reaction temperatures may be in the range of subambient temperature to ambient temperature. For example, reaction temperatures of from about -5°C to about 40°C are suitable for carrying out the methods of the present invention. Even more suitably, reaction temperatures from about 0°C to about 25°C can be used in the process of the invention. Those skilled in the art generally understand and appreciate that higher temperatures generally increase the reaction rate. Thus in some cases superambient temperatures (ie above room temperature) up to the reflux temperature of the solvent can be used.

In general, the process of the invention is carried out with an excess of base. For example, the base may be present in an amount of about 1 mol to about 10 mol relative to the compound of formula I. However, for carrying out the method of the present invention, the base may be present in an amount of about 3 mol to about 6 mol relative to the compound of formula I.

Similarly, HOSA is present in excess when compared to the compound of formula (I). It is generally advantageous to use more than a molar excess of HOSA in the process of the invention. More advantageously, it has now been found that only about a 2 molar excess of HOSA is sufficient to produce the best results by practicing the invention.

The contacting of the reaction solution prepared in steps (a) and (b) with the reactant solution obtained from step (c) can be carried out by any method known in the art. For example, but not limited thereto, said contacting in step (d) may be in a continuous reactor in which the reactants are continuously fed, or by static mixing such as static mixing with limited residence time or static mixing in combination with a loop system. Mixing, or through a microreactor. For this purpose, various known static mixers, continuous reactors and microreactors can be used. Continuous reactions can be carried out in a continuous manner or batchwise by methods well known in the art.

It is also possible to carry out the contacting in step (d) in a batch reactor. Any known reactor that produces the desired result can be used. For example, in a batch operation the reaction solutions from steps (a) and (b) are fed to a reactor containing the reaction solution from step (c), such as a stirred tank reactor. Various permutations known to those skilled in the art can be used to effect the addition of the reaction solutions in this mode of operation.

As noted above, a wide variety of nitrogen heterocyclic compounds can be used in the methods of the present invention. For example, without any limitation, compounds of formula (I) wherein R and R ₁ are hydrogen and R ₂ is methyl may be used in the methods of the invention. Compounds of formula (I) wherein R ₁ and R ₂ together with the carbon atoms to which they are attached form a benzene ring are also preferred. Specific examples of these compounds are described above. For example, substituted or unsubstituted carbazoles can be used.

In another aspect of the present invention, there is also provided another process for preparing the compound of formula II as described herein. The method of this aspect of the invention comprises the following steps. In step (a), a solution of hydroxylamine-O-sulfonic acid and a compound of formula I as described herein is prepared in a suitable organic solvent. In step (b), a solution of a suitable base is prepared in a suitable organic solvent. In step (c), the solution prepared in step (a) is simultaneously and proportionally contacted with the solution prepared in step (b) at a suitable reaction temperature to provide formula (II) in high purity and high yield compound. wherein R, R ₁ , R ₂ and m are as defined above.

Furthermore, any reactor known in the art may be used to carry out the process of the invention described above. For example, without limitation, stirred tank reactors, continuous reactors, microreactors, or static mixers may be used. The process of the invention described above is particularly suitable for carrying out the amination reaction in a continuous stirred tank reactor.

In this embodiment of the invention, any solvent suitable for carrying out the reaction may be used. More suitably, all solvents as described above can also be used in this embodiment. In general, aprotic solvents such as NMP, DMF or DMAc as described herein are more suitable solvents.

In this embodiment, the bases used are those that produce the desired results. Any known base can be used. More suitably, however, bases such as the above-mentioned organic bases may be used in this embodiment of the invention. In general, it is more suitable to use an organic base which is soluble in the reaction solvent as described above. Specific examples of organic bases suitable for this embodiment include alkali metal alkoxides such as potassium t-butoxide.

It will also be appreciated by those skilled in the art that any reaction temperature that produces the desired results may be used in this embodiment of the invention. To reiterate, as noted above, sub-ambient to ambient temperatures are generally suitable for carrying out the method of the invention. However, super-ambient temperatures may also be used in some cases.

Furthermore, it is often advantageous to carry out the process of the invention using an excess of base and HOSA when compared to the compound of formula (I). Even more advantageously, as noted above, even in this embodiment, only about a 2 molar excess of HOSA is sufficient to produce optimal results. Similarly, as described above, the base may be used in an excess of from about 1 molar to about 10 molar, but the base may be present in an amount of from about 3 molar to about 6 molar relative to the compound of formula I.

In another aspect of the present invention, there is also provided a method for preparing the compound of formula IV:

In this aspect of the invention, the method includes the following. A solution of hydroxylamine-O-sulfonic acid in a suitable organic solvent and a suitable base solution in a suitable organic solvent are simultaneously and proportionally added to the compound as described herein in a suitable organic solvent at a suitable reaction temperature. A solution of a compound of formula I wherein a compound of formula (I) as described herein is packed in a suitable reaction vessel as described above. This reaction provides compounds of formula (II) as described herein.

The resulting N-amino-indole compound (II) is then reacted with a compound of formula (III) in the same reaction vessel to provide a compound of formula (IV).

wherein R, R ₁ , R ₂ and m are as defined above, and R ₃ and R ₄ are the same or different and are independently selected from hydrogen or C ₁ -C ₄ alkyl.

In this embodiment of the invention, the amination of the compound of formula (I) to the compound of formula (II) is carried out using substantially similar procedures as described above in the other two embodiments of the invention. Thus, all of the solvents, bases and reaction vessels described above can be used in this embodiment. Similarly, the same reaction conditions as above can be used. In general, aprotic solvents such as NMP, DMF or DMAc and organic bases such as potassium tert-butoxide and HOSA in the temperature range of about -5°C to about 40°C can be employed. Temperatures from about 0°C to about 25°C are particularly preferred.

Furthermore, as mentioned above, it is often advantageous to carry out the process of the invention using an excess of base and HOSA when compared to the compound of formula (I). Even more advantageously, as noted above, even in this embodiment, only about a 2 molar excess of HOSA is sufficient to produce optimal results. Similarly, as described above, the base may be used in an excess of from about 1 molar to about 10 molar, but the base may be present in an amount of from about 3 molar to about 6 molar relative to the compound of formula I.

Advantageously, it has now been found that the reaction of a compound of formula (II) with a compound of formula (III) can be carried out by adding a compound of formula (III) in the same reaction vessel. In general, the compound of formula (III) can be added separately after the compound of formula (II) is formed. However, some organic or inorganic acid may advantageously be added. Suitable organic acids include acetic acid, propionic acid, n-butyric acid, and the like. It has also been found advantageous to use water with an organic acid. Suitable inorganic acids include hydrochloric acid, nitric acid, sulfuric acid, and the like. The acid is usually added in such an amount that the reaction medium is maintained at a pH of about 4.

The addition reaction can generally be carried out at ambient temperature, but sub-ambient to super-ambient temperatures can also be employed depending on the type of compound of formula (II) and (III) used. Generally, temperatures from about 0°C to about 100°C can be employed. A temperature of about 5°C to about 30°C is preferred. Ambient temperatures of about 20° C. are more particularly preferred.

A variety of compounds of formula (III) can be used in the method of the invention. Examples of these compounds include, but are not limited to, various well-known aldehydes and ketones. Specific examples of aldehydes include, but are not limited to, formaldehyde, acetaldehyde, propionaldehyde, n-butyraldehyde, isobutyraldehyde, benzaldehyde, phenylacetaldehyde, and the like. Suitable ketones for this method include, but are not limited to, acetone, methyl ethyl ketone, diethyl ketone, acetophenone, benzophenone, and the like. In general, aldehydes are more suitable reactants in the process of the invention, with propionaldehyde being the most suitable compound of formula (III).

In another aspect of the invention, an embodiment of the invention includes the product prepared according to the method of the invention. In particular, R, _R1 and _R4 of the product prepared according to the process of the present invention are hydrogen, _R2 is methyl, and _R3 is ethyl. More particularly, the product prepared according to the process of the present invention is 3-methyl-N-(propylidene)-1H-indol-1-amine.

Finally, in another aspect of the present invention, a method for preparing the compound of formula VI is also provided:

In this aspect of the invention, the method comprises the steps of:

In step (a) of this method embodiment of the invention, the compound of formula (IV) as described herein is first prepared substantially according to the steps of the above embodiments. That is, at a suitable reaction temperature, the hydroxylamine-O-sulfonic acid solution in a suitable organic solvent and the suitable alkali solution in a suitable organic solvent are simultaneously and proportionally added to the compound of formula I in a suitable organic solvent In solution, wherein a compound of formula (I) as described herein is packed in a suitable reaction vessel. This reaction provides compounds of formula (II) as described herein.

The resulting N-amino-indole compound (II) is then reacted with a compound of formula (III) in the same reaction vessel to provide a compound of formula (IV).

In step (b) of the process of the invention, a compound of formula (IV) is reacted with a suitable reducing agent to provide a compound of formula (V):

Finally, in step (c) of the process of the invention, a compound of formula (V) is then reacted with a compound of formula (VII) in a suitable organic solvent in the presence of a suitable base,

to provide a compound of formula (VI). Compounds of formula (VI) are optionally treated with a mineral acid such as hydrochloric acid to provide salts (eg hydrochloride salts) of compounds of formula (VI). wherein R, R ₁ , R ₂ , R ₃ , R ₄ and m are as described above. R ₅ is hydrogen, nitro, amino, halogen, C _1-4 alkyl, C _1-4 alkanoylamino, phenyl-C _1-4 alkanoylamino, phenylcarbonylamino, alkylamino or phenyl- C _1-4 alkylamino; X is halogen; n is 1 or 2 and p is 0 or 1.

It will also be understood that the steps described above are for illustration purposes only. The order in which these steps are performed may be changed and/or one or more of these steps may be performed simultaneously and/or concurrently. Accordingly, various variations of these steps also form part of the invention. More advantageously, all these steps can be carried out in the same reaction vessel as a single batch operation or in a continuous reactor.

Thus according to this aspect of the invention, in step (a) of this embodiment, in substantially the same manner as described above, by using a solvent (preferably an aprotic solvent), a base (preferably organic base) and HOSA to carry out the amination of the compound of formula (I) to form the compound of formula (II).

The compound of formula (II) thus formed is then converted to a compound of formula (IV), usually in the same reaction vessel, by reacting a compound of formula (II) with a compound of formula (III) as described above. The reaction conditions and suitable compounds of formula (III) are the same as those described above.

Compounds of formula (IV) are then reduced to compounds of formula (V), as described. This reduction can be carried out using any method known in the art. In general, this reduction can be carried out using any known C=N reducing agent such as those commonly used to reduce Schiff bases, hydrazones or imines. Examples of suitable reducing agents include, but are not limited to, lithium aluminum hydride, sodium borohydride, sodium borohydride and glacial acetic acid, sodium acetoxyborohydride, sodium diacetoxyborohydride, sodium triacetoxyborohydride, cyano Sodium borohydride, sodium ethoxide, hydrogen and catalysts, etc.

Other reducing agents such as dibutyltin hydrochloride ( _Bu2SnClH ) in HMPA can also be used. A variety of boron reagents can also be used. Specific examples include: diborane, boron-sulfide complexes such as boron-dimethylsulfide or boron-1,4-thioxane complexes; boron etherates such as boron-THF complexes; boron -Amine complexes such as boron-ammonia, boron-tert-butylamine, boron-N-ethyl-diisopropylamine, boron-N-ethylmorpholine, boron-N-methylmorpholine, boron-morpholine, boron- Piperidine, boron-pyridine, boron-triethylamine, and boron-trimethylamine; boron-phosphine complexes such as boron-tributylphosphine or boron-triphenylphosphine; mixtures of borohydrides such as sodium borohydride and tetraalkylammonium borohydride; reagents that generate boranes in situ, such as sodium borohydride and iodine, sodium borohydride and BF ₃ -diethyl etherate, sodium borohydride and chlorotrimethylsilane, tetraalkyl borohydride Combinations of ammonium and alkyl bromides such as n-butyl bromide; etc. Sodium borohydride in the presence of glacial acetic acid has generally been found to be a more suitable reducing agent in this step of the process of the invention.

This reduction reaction is likewise carried out in the presence of a suitable organic solvent. In general, aprotic polar solvents such as those described herein are more suitable for carrying out this reduction step. Specific examples of these organic solvents include, but are not limited to, NMP, DMF, DMAc, THF, heptane, hexane, toluene, petroleum ether, and the like.

It has now surprisingly been found that mixtures of polar aprotic and apolar solvents in particular offer several advantages in carrying out this reduction step. Specific examples of these solvent mixtures include, but are not limited to, NMP/heptane, NMP/hexane, NMP/petroleum ether, DMF/hexane, DMF/n-heptane, and the like. In particular, it has been found that a mixture of NMP and n-heptane can provide certain advantages in the process of the invention, since it can significantly reduce the foaming of the reagents.

The reduction of a compound of formula (IV) to a compound of formula (V) can generally be carried out at any temperature which produces the desired result. Thus, sub-ambient to ambient to super-ambient temperatures can be employed depending on the type of compound and reagent used. Generally, a temperature of from about 0°C to about 60°C is suitable. Typically a temperature of about 5°C to 40°C is employed. A temperature of about 30°C is preferred.

Compounds of formula (V) may be further isolated as suitable salts such as hydrochloride by reaction with a suitable acid such as hydrochloric acid. In general, salts of compounds of formula (V) are crystalline solids, and thus provide a means for purification, if desired, prior to conversion of compounds of formula (V) to compounds of formula (VI) in subsequent reactions with compounds of formula (VII). A method for a compound of formula (V).

The reaction of compounds of formula (V) with various pyridine derivatives of formula (VII), preferably with compounds of formula (VII) wherein X is Cl and p is 0, can be carried out to form compounds of formula (VI). Examples of such compounds of formula (VII) include, but are not limited to, 4-chloropyridine, 4-chloro-3-fluoropyridine, 4-chloro-2-fluoro-pyridine and 4-chloro-3,5-difluoropyridine.

The reaction is carried out in the aprotic polar solvent used in the previous method steps such as but not limited to NMP, DMF, DMAc, THF, heptane, hexane, toluene, petroleum ether, etc., or in a polar aprotic solvent and a nonpolar Mixtures of solvents such as but not limited to NMP/heptane, NMP/hexane, NMP/petroleum ether, DMF/hexane, DMF/n-heptane, etc. Various other solvents may also be used in this step of the method of the invention. Examples of solvents suitable for this step include: ether solvents such as bis(2-methoxyethyl) ether, diethyl ether, dimethoxy ether, dioxane or THF; polar aprotic solvents as described herein Solvents, which include DMF, DMAc, HMPA, or DMSO; or protic solvents such as methanol, ethanol, isopropanol, and the like. Additionally, any combination of mixtures of these solvents may also be used, as noted. In general, the reaction is carried out using the same solvent such as NMP or a mixture of NMP and heptane.

Suitable organic bases for this step include alkali metal alkoxides. Examples of suitable alkali metal alkoxides include, but are not limited to, lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium t-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, Potassium isopropoxide, potassium tert-butoxide, cesium methoxide, cesium ethoxide, cesium isopropoxide, cesium tert-butoxide, etc.; alkali metal hydrides such as sodium hydride or potassium hydride, etc. Mixtures of organic bases can also be used. Potassium tert-butoxide has been found to be a particularly suitable alkali metal alkoxide in carrying out this step of the process according to the invention.

The reaction of a compound of formula (V) with a pyridine derivative (VII) to form a compound of formula (VI) can generally be carried out at any temperature which produces the desired result. Thus, sub-ambient to ambient to super-ambient temperatures can be employed depending on the type of compound and reagent used. Generally, a temperature of about 70°C to about 150°C is suitable.

A compound of formula (VI) may be further reacted with a suitable mineral acid to obtain a suitable salt of the compound of formula (VI). An example of such an inorganic acid is hydrochloric acid, resulting in the hydrochloride salt of the compound of formula (VI). In general, salts of compounds of formula (VI) are crystalline solids and thus provide a means of purifying, if desired, compounds of formula (VI) prior to their use, eg, for pharmaceutical purposes.

The reaction can be carried out in the same reaction vessel or in a different vessel after the compound of formula (V) is isolated as described above. The process of the invention described above can be carried out using any reactor known in the art. Furthermore, stirred tank reactors, continuous reactors, microreactors or static mixers can be used. The process of the invention described above is particularly suitable for carrying out the coupling reaction in a static mixer with a loop system or in a continuous stirred tank reactor. Advantageously, the reaction is operated in batch mode.

In another aspect of the invention, an embodiment of the invention includes the product prepared according to the method of the invention. In particular, the product prepared was N-(n-propyl)-N-(3-fluoro-4-pyridyl)-1H-3-methylindole-1-amine hydrochloride.

In another aspect of the present invention there is also provided a compound of formula (IV), wherein said substituents are as described herein, with the proviso that when R and _R3 are hydrogen, _R4 is not hydrogen or methyl.

As stated, several compounds within the scope of formula (IV) are known and are therefore excluded from the present invention. For example, Somei et al. Tet. Lett. No. 41, pages 3605-3608 (1974) describe wherein m = 0, R ₁ , R ₂ , R ₃ = H, R ₂ = methyl, R ₄ = methyl Compounds of formula (IV), the entire content of which is hereby incorporated by reference.

In another aspect of this embodiment of the invention, suitable compounds of formula (IV) are those wherein R, _R1 and _R3 are hydrogen and _R2 is methyl. Specific compounds within the scope of the present invention include, but are not limited to, the following:

3-Methyl-N-(propylidene)-1H-indol-1-amine;

N-(propylidene)-1H-indol-1-amine;

5-Benzyloxy-N-(propylidene)-1H-indol-1-amine;

5-methoxy-N-(propylidene)-1H-indol-1-amine;

and N-(propylidene)-1H-carbazol-1-amine.

The present invention is further illustrated by the following examples, which are provided for the purpose of illustration and in no way limit the scope of the invention.

Example (General)

The following abbreviations are used in the following examples:

HOSA Hydroxylamine-O-sulfonic acid

HPLC High Performance Liquid Chromatography

KOtBu Potassium tert-butoxide

NMP N-Methylpyrrolidone

NMR nuclear magnetic resonance spectroscopy

General Analytical Techniques Used for Characterization: A variety of analytical techniques were used to characterize the compounds prepared according to the practice of this invention, these techniques included the following: ¹ H, ^{13C and19F} NMR spectra. ¹ H NMR spectral data are expressed as δ in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, and the following abbreviations are used to summarize the data: s = singlet, d = doublet; t = triplet; q = quartet; m = multiplet; dd = doublet of doublets; br = broad. HPLC data were typically collected on a Perkin-Elmer Integral 4000 liquid chromatograph using a 3.9x150 mm Waters Symmetry C ₁₈ column, 5 μ, isocratic mobile phase of acetonitrile/0.1 N ammonium formate, flow rate 1.0 mL/min and UV detection . Mass spectra were acquired on a Finnigan TSQ700 spectrometer. Elemental analysis by Robertson Microlit, Inc. Other abbreviations used herein include the following: LC = Liquid Chromatography; MS = Mass Spectrometry; EI/MS = Electron Injection Impact/Mass Spectrometer; RT = Retention Time; M ⁺ = Molecular Ion.

Example 1

1H-Indole-1-amine

Prepare 33.8 kg (32.8 kg corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) and 15.8 kg (15.6 kg corrected for 99% purity) of indole in 120.2 kg N-methylpyrrolidone ( NMP) and cooled to 0-5°C. Another solution was prepared from 67.0 kg (63.7 kg corrected for 95% purity) of potassium tert-butoxide and 122.6 kg of NMP. The amination vessel was charged with an initial charge of 47.0 kg NMP and 2.2 kg potassium tert-butoxide/NMP solution. The HOSA/indole/NMP solution and the remaining potassium tert-butoxide/NMP solution were then metered simultaneously and proportionally to the amine within 185 minutes using a metering pump system consisting of a double-ended plunger pump and a Coriolis mass flow meter together. In a container while maintaining a reaction temperature of 20-30° C., a solution containing 15.9 kg (90.2% yield) of 1H-indol-1-amine was obtained as measured by external standard HPLC analysis.

Example 2

5-Benzyloxy-1H-indole-1-amine

A solution of 5.3 kg (5.2 kg corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) in 19.1 kg of N-methylpyrrolidone (NMP) was prepared and cooled to 0-5°C. Another solution was prepared from 10.6 kg (10.0 kg corrected for 95% purity) of potassium tert-butoxide and 19.3 kg of NMP. The amination vessel was charged with an initial charge of 5.0 kg (4.7 kg corrected for 94% purity) of 5-benzyloxyindole, 15.5 kg NMP and 0.4 kg potassium tert-butoxide/NMP solution. Then within 166 minutes, the HOSA/NMP solution and the remaining potassium tert-butoxide/NMP solution were simultaneously and proportionally metered into the amination vessel while maintaining a reaction temperature of 14-29°C, and the obtained solution was measured by external standard HPLC analysis. A solution containing 4.3 kg (86.0% yield) of 5-benzyloxy-1H-indol-1-amine. After adding 105 L of water and cooling to 0-5°C, the mixture was filtered. The filtered solid was separated with 63 L of n-butyl acetate and 8.5 L of water, then filtered. The organic phase was concentrated under reduced pressure to give a solid containing 3.9 kg (77.4% yield) of 5-benzyloxy-1H-indol-1-amine as measured by external standard HPLC analysis.

Example 3

5-Methoxy-1H-indole-1-amine

A solution of 10.0 g (9.7 g corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) in 33.7 g of N-methylpyrrolidone (NMP) was prepared and cooled to 0-5°C. Another solution was prepared from 20-1 g (19.1 g corrected for 95% purity) of potassium tert-butoxide and 34.4 g NMP. An initial charge of 5.9 g 5-methoxyindole, 17.8 g NMP, and 0.7 g potassium tert-butoxide/NMP solution was charged to the amination vessel. The HOSA/NMP solution and the remaining potassium tert-butoxide/NMP solution were then metered into the amination vessel simultaneously and proportionally within 86 minutes while maintaining a reaction temperature of 15-22°C to obtain an internal standard HPLC analysis. A solution containing 5.6 g (87% yield) of 5-methoxy-1H-indol-1-amine.

Example 4

1H-carbazol-1-amine

A solution of 10.0 g (9.7 g corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) in 35.9 g of N-methylpyrrolidone (NMP) was prepared and cooled to 0-5°C. A second solution was prepared from 20.3 g (19.3 g corrected for 95% purity) of potassium tert-butoxide and 35.3 g NMP. An initial charge of 7.0 g (6.7 g corrected for 99% purity) of carbazole, 21.7 g of NMP, and 1.3 g of potassium tert-butoxide/NMP solution was charged to the amination vessel. The HOSA/NMP solution and the remaining potassium tert-butoxide/NMP solution were then metered simultaneously and proportionally into the amination vessel within 86 minutes while maintaining a reaction temperature of 22-30° C. rate of 1H-carbazol-1-amine solution.

Example 5

1H-3-Methyl-indole-1-amine

36.1% (wt/wt) was prepared by charging 35.6 kg potassium tert-butoxide and 63.1 kg N-methylpyrrolidone (NMP) into a 30 gallon Hastelloy reactor under nitrogen and then stirring at 20-25°C for 30 minutes KOtBu/NMP solution (enough for 2 amination batches). By charging 75.4 kg of NMP and a total of 17.7 kg of HOSA (in three portions over 45 minutes) under nitrogen into a 30 gallon Hastelloy reactor, stirring at 30-35°C for 40 minutes (until dissolution occurs), then cooling A 19.0% (wt/wt) solution of hydroxylamine-O-sulfonic acid (HOSA) in NMP (enough for 2 amination batches) was prepared at 10°C. The amination vessel was prepared by charging 4.5 kg (34.3 mol) of 3-methylindole, 10.0 L of NMP, and 0.4 kg (0.1 equivalents) of potassium tert-butoxide into a 30 gallon glass lined reactor under nitrogen. A proportional metering pump system consisting of a double-head plunger pump and a pair of mass flow meters was used to simultaneously pump the HOSA solution at 0.47 kg/min and the KOtBu solution at 0.49 kg/min to the amination reactor (by amination Injection tubes below the surface in the container). The temperature of the slightly exothermic amination process was controlled at 25-35°C by adjusting the jacket cooling. Feeds were stopped after 90 minutes when a total of 43.9 kg of KOtBu solution (4.1 equiv) and 42.0 kg of HOSA solution (2.1 equiv) had been fed and 97% conversion to N-amino-3-methyl- Indole conversion (analyzed by HPLC). The operation was performed in two parts. Half of the batch was transferred to a quench vessel (30 gallon reactor) containing 60 L of cold water and 12 L of toluene. The phases were separated after stirring at 20-25°C for 10 minutes. The aqueous phase was extracted with 3 x 12-L portions of toluene. The other half of the batch was processed similarly. The organic phases from each fraction of the workup were combined and concentrated (60 °C, <50 mbar, 50 L rotary evaporator) to yield 5.2 kg of N-amino-3-methylindole as a pasty solid, This corresponds to 4.5 kg of product measured by NMR corrected for solvent (3.4 wt% toluene and 6.9 wt% NMP), 89.7% yield, 95.9% pure by HPLC analysis.

Similarly, an additional amination was performed following the same procedure as above using the remaining portion of the HOSA and KOtBu solution to give 4.6 kg (corrected) N-amino-3-methylindole in 91.1% yield.

Example 6

1H-Indole-1-amine

Step 1 - Preparation of HOSA/Indole solution: 120.2 kg (116.3 L) of NMP was charged into a 50 gallon glass-lined steel reactor under nitrogen purge and slight degassing while maintaining the reactor temperature at 19-23°C . 33.8 kg (corrected to 32.8 kg for 97% purity) of HOSA was fed through the manhole at approximately 15-30 minute intervals with stirring (approximately 130 rpm) in three portions (approximately 15.8 kg, 9.0 kg and 9.0 kg). An initial exotherm of 10-15°C warming is expected. Cooling water is circulated through the jacket or gentle jacket heating is used to maintain a tank temperature of 20-35°C (preferably 30-35°C to aid dissolution). It is expected to dissolve after stirring for 1-2 hours. The contents of the reactor were cooled to a temperature of about 20°C (10-25°C) and 15.8 kg (15.6 kg corrected for 99% purity) of indole were fed through the manhole. After dissolution (minutes), the contents of the reactor were cooled to a temperature of about 0-5°C (-5 to 15°C), the agitation was reduced to about 50 rpm and the temperature was then maintained at about 0-5°C (- 5 to 15°C) for the remainder of the process.

Step 2 - Preparation of potassium tert-butoxide solution: 122.6 kg (118.7 L) of NMP was charged to a 50 gallon glass-lined steel reactor with an empty condenser tube under a nitrogen purge and slight degassing while the reactor The temperature is maintained at about 17-19°C (15-22°C). 67.0 kg (63.7 kg corrected for 95% purity) of potassium tert-butoxide (KOtBu) was fed through the manhole under stirring at about 150 rpm (100-200 rpm). A slight exotherm to 20-25°C was observed. Cool as necessary to keep the temperature below 25°C. After dissolution was achieved (within 15-60 minutes), the remainder of the process was carried out with stirring at about 50 rpm and a temperature of about 17-25°C.

Step 3 - Amination: 47.0 kg (45.5 L) of NMP was charged to a 150 gallon glass lined steel reactor under nitrogen purge and slight degassing and cooled to 10-22°C with stirring at about 180 rpm. An initial amount of about 0.05 equivalents of the KOtBu solution from step 2 (6.7 mol, total 2.2 kg of solution) was charged. The two solutions prepared above in steps 1 and 2 were then simultaneously pumped through injection tubes (3/8 inch, 304° OD) inserted in nozzles on opposite sides (about 180 degrees apart) of the top of the reactor at the following rates , SS tube): the HOSA/indole solution obtained from step 1 = 0.9 kg/min at a rate of 0.8 L/min, and the total time was 187.4 minutes; the KOtBu solution obtained from step 2 was obtained at a rate of 1.0 L/min Speed = 1.0kg/min, the total time is 187.4 minutes), while maintaining good stirring (> 180rpm) and using cooling water cooling to keep the reaction temperature at about 15-30°C, preferably 24-30°C. Reaction progress was monitored by withdrawing samples of the reaction mixture at 0.5 equivalent HOSA feed intervals (every 43 minutes, 35 seconds during simultaneous reagent feeds) for HPLC analysis as further detailed below. The simultaneous proportional feeds were continued until all reagents (133.5 mol mark) had been fed and the amination was judged to be complete as confirmed by HPLC analysis. The reactors from steps 1 and 2 were each rinsed with 5 L of NMP and the washes were pumped to the 150 gallon reactor in this step. The batch from this step was then used as is in the next step in the preparation of n-propylidene-1H-indol-1-amine.

The reaction mixture was monitored by HPLC analysis using the following conditions:

Column: Phenomenex, IB-SIL 5Phenyl, 150×4.6mm, 5 microns

Mobile phase: 65:35 0.1N ammonium formate/acetonitrile

Flow rate: 1.5mL/min

Detection: UV at 275nm

Sample preparation: Dilute approximately 15 µL of reaction mixture with 2 mL of 50:50 mobile phase mixture

Injection volume: 10μL

Example 7

N-propylidene-1H-indole-1-amine

Add about 21.6 kg of acetic acid at a rate of about 1 kg/min at a rate of about 1 kg/min at 10 to 25 ° C (preferably 10 to 18 ° C) under nitrogen purging, slight exhaust, and stirring at about 150 rpm. The procedure described in 6 was prepared in a 150 gallon steel reactor until the pH was 3.9-4.0 in 1H-indol-1-amine solution (0.1 mL reaction mixture in 5 mL water). If necessary, incrementally more HOAc was charged to maintain the pH level. Rinse the pump with about 2L of NMP. 10.8 L of water was fed essentially in one portion (approximately 1 minute addition time) (expect a slight temperature increase of approximately 3-6°C). 14.4 kg (13.9 kg corrected for a purity of 97%) of propionaldehyde is fed at about 0.8 kg/min (0.5-1.0 kg/min) while maintaining 10-24°C, preferably 10-20°C. A mild exotherm is expected. Depending on the rate of addition and cooling, a temperature increase of about 5°C is expected. Rinse the pump with about 3L of NMP. Stir at 10-24°C, preferably 17-20°C, until the reaction is judged to be complete (>99% conversion within 2-3 hours) as evidenced by HPLC analysis whose conditions are detailed further below. The progress of the reaction was monitored by taking a sample of the reaction mixture for HPLC analysis. When judged complete, the reaction was prepared to be vacuum distilled directly from the reactor into a suitable receiver. A volatile forerunt (about 45-50 L) containing tert-butanol and water is expected initially at 50-70°C and about 30-40 mm pressure. When the distillation rate slowed down, the tank temperature was gradually increased to 95-100° C., the pressure was reduced to 5-25 mm and NMP began to be collected. A total of about 320 kg of distillate was collected (to give a tank weight of 9.5 parts w/w relative to the initial indole charge), then the vacuum was released with nitrogen and cooled to 10-25°C. Distillations can be interrupted at any time if necessary or for scheduling convenience by releasing the vacuum with nitrogen, cooling to <30°C, storing under nitrogen and then restarting as needed. The reaction was carried out by charging 133 L of heptane through the reactor feed nozzle (to achieve a maximum process volume of approximately 450 L), followed by 234 L of water with cooling water to keep the exotherm temperature below 30°C. Stir for >10 minutes, then allow the phases to separate. The bottom aqueous phase was extracted with 54 L of heptane. The organic extracts were combined and washed with aqueous potassium bicarbonate (prepared from 0.6 kg potassium bicarbonate dissolved in 58 L (58-95 L) of water), followed by 58 L of water. The organic phase was concentrated to give crude N-propylidene-1H-indol-1-amine as an oil. Purified by short-path distillation with a first pass at an evaporator at about 120°C and a pressure of about 200-800 mbar to remove volatiles, followed by a second pass at an evaporator at 110°C at a pressure of 0.2-0.4 mbar to collect Purified product.

The reaction mixture was monitored by HPLC analysis using the following conditions:

Column: Phenomenex, IB-SIL 5Phenyl, 150×4.6mm, 5 microns

Mobile phase: 65:35 0.1N ammonium formate/acetonitrile

Flow rate: 1.5mL/min

Detection: UV at 275nm

Sample preparation: Add 2 drops of reaction mixture per 1 mL of acetonitrile, injection volume 10 μL

Example 8

N-(propylidene)-1H-indole-1-amine

A solution of 86.6 g (771 mmol) of potassium tert-butoxide in 160 mL of N-methylpyrrolidone (NMP) was prepared. A solution of 36.4 g (322 mmol) of hydroxylamine-O-sulfonic acid (HOSA) in 175 mL of NMP was also prepared. The HOSA solution was cooled to 10 °C after a clear solution was obtained.

In addition, a solution of 11.9 g (102 mmol) of indole in 20 mL of NMP was prepared, and an initial amount of 0.08 to 0.12 equivalent of KOtBu solution was added to the indole solution. The HOSA and KOtBu solutions were then added simultaneously and proportionally to the reaction mixture by dual syringe pumps at 20 °C within 60 min. After this addition was complete, 9 mL (500 mmol) of water, 12 mL (300 mmol) of glacial acetic acid and 15 mL (173 mmol) of propionaldehyde were added to the resulting dark brown suspension. The mixture was stirred at 20°C until the reaction was complete. The reaction mixture was then worked up by adding 500 mL of water and 200 mL of n-heptane. The phases are allowed to separate. The aqueous phase was extracted once more with 300 mL of n-heptane and twice more with 200 mL of toluene. The combined organic phases were washed twice with 100 mL of water. The resulting brown heptane solution was evaporated to dryness. This yielded 14 g of N-(propylidene)-1H-indol-1-amine (80%) as a brown liquid.

Boiling point 130-135°C (1.3-1.4 mbar)

¹ H-NMR (DMSO-d ₆ , 300 MHz, TMS) [δ, ppm]: 1.2 (t, 3H, CH ₃ ), 2.5 (m, 2H, CH ₂ ), 6.6 (d, 1H, aromatic), 7.1 (t, 1H, aromatic), 7.2 (t, 1H, aromatic), 7.6 (dd, 2H, aromatic), 8.0 (d, 1H, aromatic), 8.2 (t, 1H, NCH)

MS (EI+, 70eV): 172 [M ⁺ ], 116 [M ⁺ -NC ₃ H ₆ ]

Example 9

N-Propyl-1H-indole-1-amine

A solution of 12.3 g (69.7 mmol) of N-(propylidene)-1H-indol-1-amine in 45 mL of NMP was prepared and 1.6 g (41.8 mol) of sodium borohydride was added. A solution of 2.5 g (41.8 mmol) of glacial acetic acid in 15 mL of NMP was then prepared. The acetic acid solution was added to the above reaction mixture at 30°C over about 30 minutes. Hydrogen evolution will occur immediately. The reaction mixture was stirred at 35°C until the reaction was complete. At the end of the reaction, the reaction mixture was worked up by slowly adding 50 mL of water at 35°C. Care was taken during water addition to minimize foaming that would occur and by allowing sufficient head space for foaming. Free headspace was maintained up to three times the volume of the liquid contents of the reactor to control foaming. The reaction mixture was extracted with 50 mL of n-heptane, the phases were allowed to separate and the aqueous phase was extracted again with 25 mL of n-heptane. The combined organic phases were evaporated to dryness. This yielded 10.9 g of N-propyl-1H-indol-1-amine (90%) as a brown liquid.

Boiling point 115～125°C (1.1 mbar)

¹ H-NMR (DMSO-d ₆ , 300 MHz, TMS) [δ, ppm]: 0.9 (t, 3H, CH ₃ ), 1.35 (m, 2H, CH ₂ ), 3.0 (m, 2H, NCH ₂ ), 6.35 (d, 1H, aromatic), 6.5 (t, 1H, NH), 7.0 (t, 1H, aromatic), 7.15 (t, 1H, aromatic), 7.4 (m, 1H, aromatic), 7.5 (dd, 2H, aromatic)

MS (EI+, 70eV): 174 [M ⁺ +H], 131 [M ⁺ +H-NHC ₃ H ₇ ]

Example 10

(3-Fluoropyridin-4-yl)-(indol-1-yl)-propylamine hydrochloride

A solution of 18.0 g potassium tert-butoxide in 53 mL NMP was prepared and the suspension was stirred at 20 °C until a clear solution was obtained. The solution was cooled to -20°C. A mixture of 9.3 g (53.4 mmol) of N-propyl-1H-indol-1-amine, 7.4 g (53.4 mmol) of 4-chloro-3-fluoropyridine and 53 mL of NMP was added to the cooled solution while maintaining the internal reaction temperature at about -15°C. The reaction mixture was stirred at -20°C for about 30 minutes after the addition was complete. The reaction mixture was then added to 100 mL of water and 13 mL of HCl (37%). Then 50 mL of n-heptane (2x) was added and the phases were allowed to separate. 10 mL NaOH (32%) was added to the aqueous phase and the aqueous phase was extracted twice with 50 mL n-butyl acetate, the combined n-butyl acetate phases were washed with 50 mL water. 4.5 mL of HCl (37%) was added to the resulting n-butyl acetate phase. The mixture was distilled using a Dean-Stark trap to completely remove water. A solid precipitated during the distillation. The suspension was cooled to 5°C and filtered. 10.8 g of (3-fluoropyridin-4-yl)-(indol-1-yl)-propylamine hydrochloride (75%) remained as a pale yellow solid after drying at 60-70°C.

¹ H-NMR (DMSO d ₆ , 300 MHz, TMS) [δ, ppm]: 0.9 (t, 3H, CH ₃ ), 1.65 (m, 2H, CH ₂ ), 4.0 (dm, 2H, NCH ₂ ), 6.35 (t, 1H, aromatic), 6.7 (d, 1H, aromatic), 7.2 (m, 2H, aromatic), 7.4 (d, 1H, aromatic), 7.65 (d, 1H, aromatic), 7.7 (d, 1H, aromatic), 8.25 (d, 1H, aromatic), 8.9 (d, 1H, aromatic)

MS(CI+): 270 [M ⁺ +H, free base]

Example 11

3-Methyl-N-(propylidene)-1H-indol-1-amine

A solution of 44.7 kg (398 mol) of potassium tert-butoxide in 80 kg of N-methylpyrrolidone (NMP) was prepared. A solution of 21.5 kg (190 mol) of hydroxylamine-O-sulfonic acid (HOSA) in 98 kg of NMP was additionally prepared, and after a clear liquid was obtained the HOSA solution was cooled to 10°C.

A solution of 10 kg (76.2 mol) of 3-methylindole in 50 kg of NMP was prepared, and an initial amount of 0.08-0.12 equivalents of KOtBu solution was added to the 3-methylindole solution. The HOSA and KOtBu solutions were simultaneously and proportionally added to the reaction mixture by mass flow meter at 20° C. within 120 minutes. After the addition was complete, 6.9 L (381 mol) of water, 13.7 kg (228.6 mol) of acetic acid (100%) and 7.5 kg (129.2 mol) of propionaldehyde were added to the resulting dark brown suspension. The mixture was stirred at 20°C for about 1 hour until the reaction was complete. The reaction mixture was then worked up by adding 248 L of water and 42 kg of n-heptane. Unwanted salts precipitated from the reaction mixture. The resulting suspension was filtered and the phases were allowed to separate. The aqueous phase was extracted 3 times again with 42 kg of n-heptane. The combined organic phases were washed twice with 63 L of water. The resulting brown heptane solution was evaporated to dryness. This yielded 11.6-12.5 kg of 3-methyl-N-(propylidene)-1H-indol-1-amine as a brown liquid (81-90% yield).

Boiling point 121～123°C (1 mbar)

¹ H-NMR (300MHz, DMSO-d ₆ , TMS) [δ, ppm]: 1.15 (t, 3H, CH ₃ ), 2.3 (s, 3H, CH ₃ ), 2.45 (m, 2H, CH ₂ ), 7.05(t, 1H, aromatic), 7.2(t, 1H, aromatic), 7.5(2d, 2H, aromatic), 7.8(s, 1H, aromatic), 8.05(t, 1H, NCH)

MS ₍ CI+): 187[M ⁺⁺ H], 130[M ⁺ _-NC3H6 ]

Example 12

3-Methyl-N-propyl-1H-indol-1-amine

Prepare 3.0kg (74.4mol) sodium borohydride and 26.8kg (124mol, 86% purity) 3-methyl-N-(propylidene)-1H-indol-1-amine in 108kg NMP in 800L container solution. A solution of 4.5 kg (74.4 mol) of glacial acetic acid in 27 kg of NMP was prepared. The acetic acid solution was added to the sodium borohydride solution at 30°C over about 30 minutes. Hydrogen gas was evolved immediately. The reaction mixture was stirred at 30°C until the reaction was complete (about 1 hour). 6.3 kg of ethanol was added to the reaction mixture and foaming occurred immediately. The reaction mixture was then worked up by carefully adding an additional 80 L of water. Take care to control foaming during water addition, and it is especially recommended to add water slowly at the beginning to avoid uncontrollable foaming. Care was taken to ensure that no or only minimal foaming occurred when the first 1-2 L of water was added. The reaction mixture was left to stand overnight. The aqueous phase was extracted three times with 45 kg of n-heptane, and the combined organic phases were washed with 66 L of water. The combined organic phases were evaporated to dryness. This yielded 22.4 kg of 3-methyl-N-propyl-1H-indol-1-amine (90% yield, 94% purity) as a brown liquid.

¹ H-NMR (300MHz, DMSO d ₆ , TMS) [δ, ppm]: 0.9 (t, 3H, CH ₃ ), 1.4 (m, 2H, CH ₂ ), 2.2 (s, 3H, CH ₃ ), 2.95 (m, 2H, NCH ₂ ), 6.3 (t, 1H, NH), 7.0 (t, 1H, aromatic), 7.1 (t, 1H, aromatic), 7.15 (s, 1H, aromatic), 7.4 ( d, 1H, aromatic), 7.45 (d, 1H, aromatic)

MS ₍ CI+): 189[M ⁺⁺ H], 130[M ⁺ _-NC3H7 ]

Example 13

3-Methyl-N-propyl-1H-indol-1-amine

A solution of sodium borohydride (4.54 kg, 120 mol) in 38 kg NMP was prepared. To this solution was added a solution of 3-methyl-N-(propylidene)-1H-indol-1-amine (38.6 kg, 190 mol) in 78 kg n-heptane. A solution of 6.8 kg (120 mol) of glacial acetic acid in 32 kg of n-heptane was prepared. The acetic acid solution was added to the sodium borohydride solution using a pump over about 30 minutes at 30°C. Hydrogen evolution occurred immediately. The pump was rinsed with 3 kg of n-heptane and the wash was added to the reaction mixture. The reaction mixture was stirred at 30°C until the reaction was complete (about 1 hour). The reaction mixture was then worked up by adding 76 L of water. No foaming or only minimal foaming was observed during the addition of water. The mixture was stirred overnight and the phases were allowed to separate. Add 2.82 kg HCl (30%) and 4.75 kg water to the n-heptane phase, check the pH and add more HCl if the pH is above 1. The mixture was heated to an internal temperature of 75°C for about 2 hours. The mixture was cooled to 25°C to control the evolution of hydrogen. If there is no more residual hydrogen evolution, the pH level is adjusted to 7, an additional 30 kg of water is added, the phases are allowed to separate and the n-heptane phase is washed twice with 37 kg of water. The n-heptane phase was evaporated to dryness. This yielded 37.5 kg of 3-methyl-N-propyl-1H-indol-1-amine (98%) as a brown liquid.

Example 14

(3-fluoropyridin-4-yl)-(3-methylindol-1-yl)-propylamine hydrochloride

A solution of 58.8 kg of potassium tert-butoxide in 135.8 kg of NMP was prepared and the suspension was stirred at 20°C until a clear solution was obtained, which was referred to as solution A.

A solution of 36.1 kg (175.6 mol) of 3-methyl-N-propyl-1H-indol-1-amine and 24.3 kg (184.4 mol) of 4-chloro-3-fluoropyridine in 68.5 kg of NMP was prepared, which was Call it solution B.

The two solutions A and B prepared as above were added simultaneously (approximately 24 kg/h solution A and approximately 17.2 kg/h solution B) into the reactor previously filled with 15 kg NMP and 2 kg solution A while maintaining the internal temperature at -20 ℃. The liquid volume in the reaction vessel was kept steady at the same level during the complete addition of solutions A and B by passing the mixed solution into another vessel. The reaction solution thus collected in another vessel was quenched with 19 kg of water. The reactor was washed with 20 kg NMP after adding the full amount of solutions A and B. For further work-up, 275 kg of water were added and the basic aqueous phase was extracted 4 times with 57 kg of n-heptane. The combined n-heptane phases were extracted twice with 175 kg water and 13.2 kg HCl (30%), the phases were allowed to separate and 30.9 kg NaOH solution (33%) was added to the aqueous phase. The aqueous phase was extracted twice with 155 kg of n-butyl acetate and the combined n-butyl acetate phases were washed with 176 kg of water. A sample of the n-butyl acetate extract was taken for free base analysis. Based on this analysis, the n-butyl acetate phase was diluted to contain about 10% free base (w/w). The water was removed under vacuum and 18.5 kg HCl (30%) was added to the resulting n-butyl acetate phase. The mixture was distilled using a Dean-Stark trap to completely remove water. A solid precipitated during the distillation. The suspension was cooled to 5°C and filtered. Wash the filter cake twice with 76kg n-butyl acetate. After drying at 60-70° C. 43.8 kg (3-fluoropyridin-4-yl)-(3-methylindol-1-yl)-propylamine hydrochloride (77.3%) remained as a pale yellow solid.

Melting point 219°C (DSC, heating rate 5°C/min, HCl loss and decomposition)

¹ H-NMR (300 MHz, DMSO-d ₆ , TMS) [δ, ppm]: 0.9 (t, 3H, CH ₃ ), 1.7 (m, 2H, CH ₂ ), 2.5 (m, 3H, CH ₃ ), 4.0 (dm, 2H, CH ₂ ), 6.3 (m, 1H, aromatic), 7.2 (m, 2H, aromatic), 7.3 (m, 1H, aromatic), 7.4 (d, 1H, aromatic), 7.7 (dd, 1H, aromatic), 8.2 (d, 1H, aromatic), 8.9 (d, 1H, aromatic)

MS (EI+, 70eV): 283[M ⁺ , free base], 240[M ⁺ -C ₃ H ₇ ], 130[3-methylindole fragment], 96[fluoropyridine fragment]

Example 15

4-Chloro-3-fluoropyridine

2.5 kg (25.8 mol) of 3-fluoropyridine, 3.4 kg (29.6 mol, 1.2 equiv) of tetramethylethylenediamine (TMEDA), and 20 L of methyl tert-butyl ether (MTBE) were charged to a 30 gallon Hastelloy reaction under nitrogen device. The solution was cooled to -50°C. A total of 15.5 L (12.6 L, 29.6 mol, 1.15 equiv) of 1.9 M lithium diisopropylamide (LDA) solution (heptane/THF/ethylbenzene) was added over 24 minutes while maintaining -40 to -48 °C temperature. The beige suspension was stirred at -44 to -48°C for 50 minutes. A solution of 7 kg (29.6 mol, 1.15 equiv) of hexachloroethane in 20 L of MTBE was added over 48 minutes while maintaining a temperature of -40 to -46°C. After stirring at -40°C for 20 minutes the reaction was warmed to 0°C and then quenched into a reactor containing 54 L of cold water. After stirring at 20-25° C. for 20 minutes, the mixture was filtered through celite to break a fine emulsion. The layers were separated. The aqueous layer was extracted with 5L MTBE. The organic layers were combined and extracted with several portions (1 x 21 L, 3 x 13 L) of 2N HCl. The acidic aqueous phases were combined, separated with 16 L of MTBE, and then basified to pH 6.19 by adding 6.5 kg of 50% NaOH while maintaining a temperature of 15-20 °C. The layers were separated. The aqueous phase was extracted with 10 L MTBE. The combined organic phases were dried over 3.0 kg sodium sulfate, then filtered and concentrated (56 °C, 575 mbar during most of the concentration, 400 mbar for the final concentration) to give 3.7 kg of 4- Chloro-3-fluoropyridine, 2.4 kg corrected for 31.2% solvent by NMR, 95.5% pure by HPLC, 70.2% yield.

Example 16

(3-fluoropyridin-4-yl)-(3-methylindol-1-yl)-propylamine hydrochloride

A solution of 510 g (4.5 mol) of potassium tert-butoxide in 1190 g of NMP was prepared and the suspension was stirred at 20° C. until a clear solution was obtained (solution A).

Preparation of 154.1 g (769 mmol, 94% purity) of 3-methyl-N-propyl-1H-indol-1-amine, 112.7 g (846 mmol, 99% purity) of 4-chloro-3-fluoropyridine and 622 g of NMP solution (Solution B).

950 g of solution A were charged to a loop system connected to a continuous stirred tank reactor (CSTR) and a static mixer with a ring pump. The loop system was cooled to -15°C. The CSTR was initially charged with solution A and solution B from the static mixer, both solutions were added under temperature control (-15°C) for 53 minutes. The volume in the CSTR was kept constant at about 360 mL during the addition. The reaction mixture was quenched with 247 g of water. After the feed was complete the loop system was emptied and the system was washed with 951 g of water. An additional 1224 g of water was added to the washes and quenched reaction solution. The aqueous phase was extracted 4 times with 380 g of n-heptane. The resulting n-heptane phase was extracted twice with a solution of 771 g of water and 45.4 g of HCl (37%). To the resulting aqueous phase was added 131 g of NaOH (33%) and extracted twice with 680 g of n-butyl acetate. The resulting n-butyl acetate phase was washed once with 775 g of water. 79.6 g HCl (37%) was added and the resulting mixture was distilled under vacuum using a Dean-Stark trap until no more water was removed. The reaction mixture was cooled to 5°C when the product started to crystallize, and the product was filtered. Dry under vacuum in a tray dryer. This gave 164.4 g of 3-fluoropyridin-4-yl-(3-methylindol-1-yl)-propylamine hydrochloride (71% yield).

Example 17

N-(propylidene)-1H-indole-1-amine

A solution of 26.8 kg (239 mol) potassium tert-butoxide (KOtBu) in 50 kg N-methylpyrrolidone (NMP) was prepared. A solution of 13.8 kg (120 mol) of hydroxylamine-O-sulfonic acid (HOSA) in 71 kg of NMP was additionally prepared and the HOSA solution was cooled to 10° C. after obtaining a clear liquid.

A solution of 6.4 kg (54.6 mol) of indole in 25 kg of NMP was prepared. The HOSA and KOtBu solutions prepared above were simultaneously and proportionally added to this solution by mass flow meter within 180 minutes, and the reaction mixture was kept at 15°C. To the resulting dark brown suspension were added 4.3 L (239 mol) of water, 9.7 kg (161.5 mol) of acetic acid (100%) and 5.3 kg (91.3 mol) of propionaldehyde after the addition had ended. The mixture was stirred at 20°C for about 1 hour until the reaction was complete. The reaction mixture was then worked up by adding 180 L of water and 21 kg of n-heptane. Unwanted salts precipitated from the reaction mixture. The resulting suspension was filtered and the phases were allowed to separate. The aqueous phase was extracted 4 times again with 21 kg of n-heptane. The combined organic phases were washed twice with 45 L of water. The resulting brown heptane solution was evaporated to a 15-25% solution. This yielded 6.3-7.0 kg of N-(propylidene)-1H-indol-1-amine as a brown liquid (67-74% yield corrected for 19.7-24.1% assay).

¹ H-NMR (400MHz, DMSO-d ₆ , TMS) [δ, ppm]: 1.19 (t, 3H, CH ₃ ), 2.48 (m, 2H, CH ₂ ), 6.60 (d, 1H, aromatic), 7.08 (t, 1H, aromatic), 7.22 (t, 1H, aromatic), 7.57 (d, 1H, aromatic), 7.61 (d, 1H, aromatic), 8.03 (d, 1H, aromatic), 8.19 (t, 1H, NCH)

MS(ES+): 173[M ⁺⁺ H], 117[M ⁺ -NC ₃ H ₆ ]

Example 18

N-Propyl-1H-indole-1-amine

A solution of 0.83 kg (21.9 mol) sodium borohydride in 16.6 kg NMP was prepared. Add 31.9kg

N-(propylidene)-1H-indol-1-amine as a 19.7% solution in n-heptane (36.5 mol) and an additional 7.7 kg of n-heptane. A solution of 1.32 kg (21.9 mol) of glacial acetic acid in 2.8 kg of n-heptane was prepared. The acetic acid solution was added to the sodium borohydride solution using a pump over about 30 minutes at 30°C. Hydrogen evolution will occur immediately. Wash the pump with 2 kg of n-heptane. The reaction mixture was stirred at 30°C until the reaction was complete (about 1 hour). The reaction mixture was worked up by adding 20 L of water. No foaming or only minimal foaming was observed during the addition of water. The mixture was stirred overnight and the phases were allowed to separate. Add 0.9 kg HCl (30%) and 3.4 kg water to the n-heptane phase and check if the pH is below 1. Additional amounts of HCl were added to adjust the pH to approximately 1, if necessary. The mixture was heated to an internal temperature of 75°C for about 2 hours. The mixture was cooled to 25°C to control evolution of residual hydrogen. If there is no more residual hydrogen evolution, an additional 20.3 kg of water are added and the pH is adjusted to a level >7 with NaOH (33%). The phases were allowed to separate and the n-heptane phase was washed with 20.3 kg of water. The n-heptane phase was evaporated to dryness. This yielded 5.84 kg of N-propyl-1H-indol-1-amine (82.6%) as a brown liquid.

¹ H-NMR (400MHz, DMSO-d ₆ , TMS) [δ, ppm]: 0.91 (t, 3H, CH ₃ ), 1.35 (m, 2H, CH ₂ ), 3.00 (m, 2H, CH ₂ ), 6.33 (d, 1H, aromatic), 6.43 (t, 1H, NH), 7.12 (t, 1H, aromatic), 6.98 (t, 1H, aromatic), 7.35 (d, H, aromatic), 7.46 (d, 1H, aromatic), 7.50 (d, 1H, aromatic)

MS(ES+): 175[M ⁺⁺ H]

Example 19

Indol-1-yl-propyl-pyridin-4-yl-amine hydrochloride

A solution of 12.4 kg (110.7 mol) of potassium tert-butoxide in 23.6 kg of NMP was prepared and the suspension was stirred at 20° C. until a clear solution was obtained (solution A).

Prepare 5.84kg) 27.7mol, analytical result 82.6%) N-propyl group-1H-indol-1-amine and 4.36kg (29.1mol) the second solution (solution B) of 4-chloropyridine hydrochloride in 15kg NMP ).

Solution A was added to solution B while maintaining the temperature at 20°C. Stir for 1 hour and check for completion of the reaction. The reaction mixture was quenched in 135 kg of water. The pH of the solution was adjusted to about 2 with HCl (30%) and extracted twice with 20 kg n-heptane. Remove the organic layer. The pH of the aqueous layer was adjusted to 12 with NaOH (33%) and extracted twice with 16 kg n-butyl acetate. Remove the aqueous layer. The organic layer was washed with 23 kg of water. 10.8 kg methanolic HCl (29.9 mol, analysis 10.1%) was added to the organic layer at 20°C. After crystallization the mixture was cooled to 5°C, the product was filtered and washed with n-butyl acetate. Dry in a tray dryer under vacuum at 80°C. This will yield 5.8 kg of indol-1-yl-propyl-pyridin-4-yl-amine hydrochloride as a white to beige solid (73% yield).

¹ H-NMR (400MHz, DMSO-d ₆ , TMS) [δ, ppm]: 0.94 (t, 3H, CH ₃ ), 1.62 (m, 2H, CH ₂ ), 4.05 (dm, 2H, CH ₂ ), 6.74 (d, 1H, aromatic), 7.19 (m, 1H, aromatic), 7.28 (m, 1H, aromatic), 7.30 (d, 1H, aromatic), 5.8～7.6 (sv br, 2H, aromatic family), 7.63 (d, 1H, aromatic), 7.70 (d, 1H, aromatic), 8.43 (d br, 2H, aromatic), 15.2 (s br, 1H, NH ⁺ )

MS(ES+): 252 [M ⁺ +H, free base]

The following examples illustrate N-aminated products obtained by following the procedure described in EP0249452.

Comparative example 1

1H-Indole-1-amine

A solution of 3.3 g (3.2 g corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) in 7.7 g of water was prepared and cooled to 0-5°C. 10.0 g of indole and 50.0 g of water were charged to the amination vessel. The HOSA/water solution and 7.3 mL of 30% NaOH solution were then simultaneously metered into the amination vessel within 120 minutes while maintaining a reaction temperature of 20-25°C. HPLC analysis indicated no formation of 1H-indole-1-amine.

While the invention has been illustrated by certain preceding examples, it is not to be considered as limited thereby; rather, the invention encompasses the general scope as disclosed hereinabove. Various changes and embodiments can be made without departing from its spirit and scope.

Claims (55)

1. the method for a preparation formula II compound,

It may further comprise the steps:

(a) preparation hydroxylamine-o-sulfonic acid solution in appropriate organic solvent;

(b) solution of preparation appropriate base in appropriate organic solvent;

(c) solution of preparation I compound in appropriate organic solvent;

(d) under suitable reaction temperature will from the described solution of described step (a) with from the described solution of described step (b) be contained in suitable reaction vessel in from the described solution of step (c) simultaneously and contact pro rata, thereby provide described formula (II) compound with high purity and high yield;

Wherein

R is hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, benzyloxy or formula C _nH _xF _yOr OC _nH _xF _yFluoroalkyl or Fluoroalkyloxy, wherein n is 1～4 integer, x is 0～8 integer, y is 1～9 integer, and the summation of x and y is 2n+1;

R ₁And R ₂Identical or different and be independently from each other hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, benzyloxy or formula C _nH _xF _yOr OC _nH _xF _yFluoroalkyl or Fluoroalkyloxy, wherein n is 1～4 integer, x is 0～8 integer, y is 1～9 integer, and the summation of x and y is 2n+1; Perhaps

R ₁And R ₂The carbon atom that connects with them forms C ₅-C ₈Ring; With

M is 1 or 2.

According to the process of claim 1 wherein described step (a) and (b) in described solvent be aprotic solvent.

3. according to the method for claim 2, wherein said aprotic solvent is a N-Methyl pyrrolidone.

4. according to the method for claim 2, wherein said solvent is N, dinethylformamide.

5. according to the method for claim 2, wherein said solvent is a N,N-dimethylacetamide.

6. according to the process of claim 1 wherein that the described alkali in the described step (b) is organic bases.

7. according to the method for claim 6, the pKa value of wherein said alkali is identical with indoles at least approximately.

8. according to the method for claim 6, wherein said organic bases is an alkali metal alcoholates.

9. method according to Claim 8, wherein said alkali metal alcoholates is selected from: lithium methoxide, lithium ethoxide, Virahol lithium, trimethyl carbinol lithium, sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide, potassium methylate, potassium ethylate, potassium isopropoxide, potassium tert.-butoxide, methyl alcohol caesium, ethanol caesium, Virahol caesium and trimethyl carbinol caesium.

10. method according to Claim 8, wherein said alkali metal alcoholates is a potassium tert.-butoxide.

11. according to the process of claim 1 wherein that the described solvent in the described step (c) is an aprotic solvent.

12. according to the method for claim 11, wherein said aprotic solvent is a N-Methyl pyrrolidone.

13. according to the method for claim 11, wherein said aprotic solvent is N, dinethylformamide.

14. according to the method for claim 11, wherein said aprotic solvent is a N,N-DIMETHYLACETAMIDE.

15. according to the process of claim 1 wherein that described temperature of reaction is-5 ℃ to about 40 ℃ approximately.

16. according to the process of claim 1 wherein that described temperature of reaction is about 0 ℃ to about 25 ℃.

17. according to the process of claim 1 wherein that described alkali exists with the amount of about 1mol～about 10mol with respect to described formula I compound.

18. according to the process of claim 1 wherein that described alkali exists with the amount of about 3mol～about 6mol with respect to described formula I compound.

19. according to the process of claim 1 wherein that the described contact in the described step (d) undertaken by static mixing.

20. according to the process of claim 1 wherein that the described contact in the described step (d) undertaken by flow reactor.

21. according to the process of claim 1 wherein that the described contact in the described step (d) carries out in batch reactor.

22. according to the process of claim 1 wherein R and R ₁Be hydrogen and R ₂It is methyl.

23. according to the process of claim 1 wherein R ₁And R ₂The carbon atom that connects with them forms phenyl ring.

24. the method for a preparation formula II compound,

It may further comprise the steps:

(a) solution of preparation hydroxylamine-o-sulfonic acid and formula I compound in appropriate organic solvent;

(b) solution of preparation appropriate base in appropriate organic solvent;

(c) will be under suitable reaction temperature from the described solution of described step (a) with simultaneously and contact pro rata from the described solution of described step (b), thus described formula (II) compound provided with high purity and high yield;

Wherein

R is hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, benzyloxy or formula C _nH _xF _yOr OC _nH _xF _yFluoroalkyl or Fluoroalkyloxy, wherein n is 1～4 integer, x is 0～8 integer, y is 1～9 integer, and the summation of x and y is 2n+1;

R ₁And R ₂Identical or different and be independently from each other hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, benzyloxy or formula C _nH _xF _yOr OC _nH _xF _yFluoroalkyl or Fluoroalkyloxy, wherein n is 1～4 integer, x is 0～8 integer, y is 1～9 integer, and the summation of x and y is 2n+1;

Perhaps

R ₁And R ₂The carbon atom that connects with them forms C ₅-C ₈Ring; With

M is 1 or 2.

25. the method for a preparation formula IV compound,

This method comprises:

Hydroxylamine-o-sulfonic acid solution that will be in suitable organic solvent under suitable reaction temperature and the suitable alkaline solution in suitable organic solvent are simultaneously and join pro rata in the solution of the formula I compound in suitable organic solvent so that formula (II) compound to be provided, wherein said formula (I) compound is installed in the suitable reaction vessel

And with described formula (II) compound in described reaction vessel with formula (III) compound reaction so that formula (IV) compound to be provided,

Wherein

R is hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, benzyloxy or formula C _nH _xF _yOr OC _nH _xF _yFluoroalkyl or Fluoroalkyloxy, wherein n is 1～4 integer, x is 0～8 integer, y is 1～9 integer, and the summation of x and y is 2n+1;

R ₁And R ₂Identical or different and be independently from each other hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, benzyloxy or formula C _nH _xF _yOr OC _nH _xF _yFluoroalkyl or Fluoroalkyloxy, wherein n is 1～4 integer, x is 0～8 integer, y is 1～9 integer, and the summation of x and y is 2n+1;

R ₃And R ₄Identical or different and be independently from each other hydrogen or C ₁-C ₄Alkyl; With m be 1 or 2.

26. according to the method for claim 25, wherein said solvent is an aprotic solvent.

27. according to the method for claim 26, wherein said aprotic solvent is a N-Methyl pyrrolidone.

28. according to the method for claim 26, wherein said aprotic solvent is N, dinethylformamide.

29. according to the method for claim 26, wherein said aprotic solvent is a N,N-dimethylacetamide.

30. according to the method for claim 25, wherein said alkali is organic bases.

31. according to the method for claim 30, wherein said organic bases is an alkali metal alcoholates.

32. according to the method for claim 31, wherein said alkali metal alcoholates is selected from: lithium methoxide, lithium ethoxide, Virahol lithium, trimethyl carbinol lithium, sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide, potassium methylate, potassium ethylate, potassium isopropoxide, potassium tert.-butoxide, methyl alcohol caesium, ethanol caesium, Virahol caesium and trimethyl carbinol caesium.

33. according to the method for claim 31, wherein said alkali metal alcoholates is a potassium tert.-butoxide.

34. according to the method for claim 25, wherein said temperature of reaction is-5 ℃ to about 40 ℃ approximately.

35. according to the method for claim 25, wherein said temperature of reaction is about 0 ℃ to about 25 ℃.

36. according to the method for claim 25, wherein with respect to described formula I compound, described alkali exists with the amount of about 1mol～about 10mol.

37. according to the method for claim 25, wherein with respect to described formula I compound, described alkali exists with the amount of about 3mol～about 6mol.

38. according to the method for claim 25, wherein R, R ₁And R ₄Be hydrogen, R ₂Be methyl, and R ₃It is ethyl.

39. the method for a preparation formula VI compound or its suitable salt,

It may further comprise the steps:

(a) hydroxylamine-o-sulfonic acid solution that will be in suitable organic solvent under suitable reaction temperature and the appropriate base solution in suitable organic solvent are simultaneously and join pro rata in the solution of the formula I compound in suitable organic solvent so that formula (II) compound to be provided, wherein said formula (I) compound is installed in the suitable reaction vessel

And with described formula (II) compound in described reaction vessel with formula (III) compound reaction so that formula (IV) compound to be provided;

(b) described formula (IV) compound and appropriate reductant are reacted so that the formula V compound to be provided;

(c) in appropriate organic solvent in the presence of suitable alkali with described formula V compound and formula (VII) compound

Reaction to be to provide formula (VI) compound, randomly with itself and suitable inorganic acid reaction so that the salt of formula (VI) compound to be provided;

Wherein

R is hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, benzyloxy or formula C _nH _xF _yOr OC _nH _xF _yFluoroalkyl or Fluoroalkyloxy, wherein n is 14 integer, x is 0～8 integer, y is 1～9 integer, and the summation of x and y is 2n+1;

R ₁And R ₂Identical or different and be independently from each other hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, benzyloxy or formula C _nH _xF _yOr OC _nH _xF _yFluoroalkyl or Fluoroalkyloxy, wherein n is 1～4 integer, x is 0～8 integer, y is 1～9 integer, and the summation of x and y is 2n+1; Perhaps

R ₃And R ₄Identical or different and be independently from each other hydrogen or C ₁-C ₄Alkyl; With m be 1 or 2;

R ₅Be hydrogen, nitro, amino, halogen, C _1-4Alkyl, C _1-4Alkanoylamino, phenyl-C _1-4Alkanoylamino, phenylcarbonyl group amino, alkylamino or phenyl-C _1-4Alkylamino;

X is a halogen;

M and n are 1 or 2, and p is 0 or 1.

40. according to the method for claim 39, the described reductive agent in the wherein said step (b) is a sodium borohydride.

41. according to the method for claim 39, described being reflected in the appropriate organic solvent in the wherein said step (b) carried out.

42. according to the method for claim 41, wherein said solvent is an aprotic polar solvent.

43. according to the method for claim 41, wherein said solvent is N-Methyl pyrrolidone, N, dinethylformamide, N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), heptane, hexane, toluene, sherwood oil or its mixture.

44. according to the method for claim 41, wherein said solvent is the mixture of N-Methyl pyrrolidone or N-Methyl pyrrolidone and normal heptane.

45. according to the method for claim 39, the described temperature of reaction in the wherein said step (a) is-70 ℃ to about 150 ℃ approximately.

46. according to the method for claim 39, the described temperature of reaction in the wherein said step (a) is-20 ℃ to about 15 ℃ approximately.

47. according to the method for claim 39, the described alkali in the wherein said step (c) is potassium tert.-butoxide.

48. according to the method for claim 39, wherein said step (c) is undertaken by static mixer.

49. according to the method for claim 39, wherein said step (c) is carried out in the continous way stirred-tank reactor.

50. according to the method for claim 39, wherein said step (c) is carried out in batch reactor.

51. according to the method for claim 39, wherein said step (c) is carried out in microreactor.

52. according to the method for claim 39, wherein said step (c) with circuit system in the continous way stirred-tank reactor of static mixer combination in carry out.

53. formula (IV) compound or its enantiomorph, steric isomer or mixture, its tautomer or the acceptable salt of its medicine, solvate or derivative:

Wherein

R is hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, benzyloxy or formula C _nH _xF _yOr OC _nH _xF _yFluoroalkyl or Fluoroalkyloxy, wherein n is 1～4 integer, x is 0～8 integer, y is 1～9 integer, and the summation of x and y is 2n+1;

R ₁And R ₂Identical or different and be independently from each other hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, benzyloxy or formula C _nH _xF _yOr OC _nH _xF _yFluoroalkyl or Fluoroalkyloxy, wherein n is 1～4 integer, x is 0～8 integer, y is 1～9 integer, and the summation of x and y is 2n+1; Perhaps

R ₁And R ₂The carbon atom that connects with them forms C ₅-C ₈Ring;

R ₃And R ₄Identical or different and be independently from each other hydrogen or C ₁-C ₄Alkyl; With m be 1 or 2;

Condition is as R and R ₃When being hydrogen, R ₄Not hydrogen or methyl.

54. according to the compound of claim 53, wherein R, R ₁And R ₃Be hydrogen, R ₂It is methyl.

55. according to the compound of claim 53, it is selected from following material:

3-methyl-N-(propylidene base)-1H-indoles-1-amine;

N-(propylidene base)-1H-indoles-1-amine;

5-benzyloxy-N-(propylidene base)-1H-indoles-1-amine;

5-methoxyl group-N-(propylidene base)-1H-indoles-1-amine; With

N-(propylidene base)-1H-carbazole-1-amine.